(360b) Implementation of a Process Intensification Approach in the Production of an API Intermediate

Organic synthesis is essential for the production of an important class of pharmaceuticals and its implementation on an industrial scale is a great challenge for the modern pharmaceutical industry. The majority of processes are currently based on batch and semi-batch processes, but besides their wide flexibility and versatility, they face considerable disadvantages. Examples are long reaction sequences, then occurrence of non-uniform conditions inside the vessels, limited potential to apply real time process monitoring, difficulties in automating the production, and so on. Furthermore, requirements to store intermediates and complicated cleaning procedures are activities that should be minimized in order to achieve the most profitable production of active pharmaceutical ingredients (APIs).

Continuous manufacturing of pharmaceuticals is one of the most suitable ways to avoid the typical problems associated with batch processing. These processes are eco-friendly and economical, including better usage of raw materials, smaller waste production, less energy consumption, higher throughput, improved yields, better temperature profiles inside chemical reactors, and so on. In addition, a high degree of automation and process controllability can be achieved and therefore the Process Analytical Technology (PAT) Initiative may be implemented in a very efficient way. 

The main focus here is on one intermediate step in the production of Zuclopenthixol, a product of H. Lundbeck A/S. Dehydration of 9‐Allyl‐2‐Chlorothioxanthen‐9‐Ol (“N714-Allylcarbinol”) into cis/trans 9H‐thioxanthene,2‐chloro‐9‐(2‐propenylidene)‐(9CI) (“N746-Butadienes”) is a manufacturing step that was traditionally performed in batch mode with quite long reaction times and plenty of difficulties hindering successful implementation of a PAT strategy. Performed in this way, the dehydration step required several supportive operations that were defined as non-value added activities (NVAs). More precisely, storage of substrates and products, as well as a solvent swap from tetrahydrofuran to toluene were neccesary in the traditional production of Zuclopenthixol.

Avoiding NVAs in such manufacturing step is here achieved by implementing a process intensification approach. More precisely, a switch from lab-scale batch processing to a high-pressure mesoscale laminar tubular reactor is performed. A pressure increase enables higher reaction temperature and therefore shorter reaction times. Furthermore, better mass and heat transfer in tubular reactors additionally allowed faster manufacturing of “N746-Butadienes”. As a consequence, the chemical reaction was accelerated from 3 hours in batch mode to just 3 min in the tubular laminar reactor (considering total conversion of “N714-Allylcarbinol”). 

In addition to a new process design, successful implementation of real-time process monitoring was performed as well. The main focus is on in-line FT-NIR analysis that is validated with at-line FT-NIR and off-line HPLC analyses. Such monitoring is achieved by implementing a process chemometrics approach based on successful development of a Partial Least Squares (PLS) regression calibration model for the spectroscopic data. Very fast data acquisition is achieved, resulting in faster development of process understanding.

Furthermore, detailed analysis of substrates and products is performed in order to check the purity of these constituents. It was discovered that the presence of hydronium ions has a strong influence on the occurrence of side reactions. More precisely, high molar concentrations of Brøndsted acids caused the formation of undesired polymers in the reaction system caused by the opening of tetrahydrofuran rings. Chemical reactions between open rings were noticed and validated by using Size Exclusion Chromatography (SEC) and NMR spectroscopy. 

Process intensification of the intermediate manufacturing step in the Zuclopenthixol production was successfully implemented by a transfer of the lab-scale batch process to a mesoscale tubular laminar reactor. Acceleration of the chemical reaction indeed allowed usage of mesoscale laminar reactors, combined with fast and accurate in-line process monitoring. The occurrence of side reactions was identified and changes in the overall Zuclopenthixol production were suggested. For instance, immediate neutralization of the hydronium ions after the dehydration reaction is considered to be necessary as a future work.